This is a single arm, open label Phase II study of MPDL3280A, an anti-PD-L1 antibody administered as neoadjuvant therapy to subjects with either BCG-refractory non-muscle invasive transitional cell carcinoma (TCC) of the bladder, or muscle-invasive TCC appropriate for cystectomy and refusing or ineligible for neoadjuvant chemotherapy. Enrolled patients will be assigned sequentially to dose levels in cohorts of 6 patients per dose level. The starting dose level is 1200mg x 1 dose and will be escalated in subsequent cohorts to 1200mg q 3 weeks x 2 doses, and finally 1200mg q 3 weeks x 3 doses to determine the impact of increasing number of treatments on the modulated immune response with the tumor tissue. Subjects with adverse pathology (pT3/pT4 or N+) will be offered the option of adjuvant MPDL3280A for up to 16 cumulative cycles of treatment. After all neoadjuvant study therapy is administered, each subject will undergo cystectomy to evaluate pathologic response to treatment and for immunologic characterization in the resected tissue. Serum and urine will be obtained as well to characterize circulating immune responses. After the multi-dose portion of the study has completed accrual two expansion cohorts of up to 15 patients each with NMIBC or MIBC will be accrued at the highest dose level for further characterization of safety, efficacy, and immunologic analysis. Patients with pT3, pT4, or N+ disease at the time of cystectomy and no metastatic disease will be offered the option of adjuvant MPDL3280A for up to a total of 16 cumulative cycles. All subjects will be followed clinically for up to 2 years to assess for disease recurrence.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||Start Date: April 2016||Phase 2||Interventional|
Primary Outcome 1 - Measure: Change in CD3+ T cell count/µm2
Primary Outcome 1 - Time Frame: Up to 1 year
Primary Outcome 2 - Measure: Pathologic T0 rate
Primary Outcome 2 - Time Frame: procedure
- 18 years of age or older
- ECOG performance status 0, 1
- Histologically document transitional cell carcinoma with the presence of any of the
following stages: CIS, high-grade Ta, any grade T1, or any grade cT2-T4, considered
appropriate for radical cystectomy. Subjects with mixed histology are required to have
a dominant TCC pattern.
- For subjects with NMIBC, BCG-refractory or BCG-resistant disease. BCG-refractory
disease is defined as the absence of a complete response by 6 months in patients who
have received induction and maintenance OR two induction courses of BCG. BCG-resistant
disease is defined as persistent or recurrent disease after 2 induction courses of BCG
within 1 year OR cancer recurrence within 1 year of initiation of therapy for patients
who have received induction plus maintenance BCG therapy. Subjects with NMIBC must be
suitable for and willing to undergo a radical cystectomy at the completion of study
- For subjects with muscle invasive disease: not suitable neoadjuvant cisplatin-based
chemotherapy as determined by the following:
- Creatinine clearance less than 60ml/min. GFR should be assessed by calculation from
serum/plasma creatinine (Cockcroft-Gault formula)
- CTCAE Gr >/= 2 hearing loss
- CTCAE Gr >/= 2 neuropathy
- Subjects with MIBC not meeting the above criteria are still eligible provided the
patient declines neoadjuvant cisplatin-based chemotherapy, after specific informed
consent describing the known benefits of cisplatin-based chemotherapy. The reason for
declining must be documented.
- Adequate bone marrow function defined as
- WBC > 2500 cells/mm3
- ANC > 1500 cells/mm3
- Hemoglobin > 9 g/dL. Patients may be transfused or receive erythropoietic treatment to
meet this criterion.
- Platelet count > 100,000 cells/mm3
- Adequate renal function: Serum creatinine < 2 mg/dL OR calculated CrCl > 30ml/min
- Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert's disease)
- AST and ALT < 2.5 x ULN
- Ability to understand and willingness to sign a written informed consent.
- Have available evaluable archival tumor tissue for PD-L1 biomarker assessment.
Presence of PD-L1 antigen on tumors is NOT required for study entry.
- The effects of MPDL3280A on the developing human fetus are unknown. For this reason
women of child-bearing potential and men must agree to use adequate contraception
prior to study entry, during study participation, and for 90 days after study
treatment discontinuation. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and for 90 days after completion of study drug administration.
- Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the
bladder are not allowed.
- Known distant metastatic disease (e.g. pulmonary or hepatic metastases).
- Subjects with malignant lymphadenectomy in the abdomen or pelvis considered
appropriate for radical cystectomy and lymphadnectomy with the goal of complete
resection of all malignant disease are allowed.
- Intravesical chemo- or biologic therapy within 6 weeks of first treatment.
- Prior systemic chemotherapy for transitional cell carcinoma of the bladder.
- Subjects who have received prior intravesical chemotherapy are allowed.
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti CTLA-4, anti-PD1 and anti-PD-L1 therapeutic antibodies.
- History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,
multiple sclerosis, vacuities, or glomerulonephritis.
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone are eligible for this study.
- Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen
are eligible for this study.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan.
- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Chronic liver disease
- HIV or active hepatitis B virus (HBV; chronic or acute; defined as having a positive
hepatitis B surface antigen [Bag] test at screening) or active hepatitis C
- Patients with past HBV infection or resolved HBV infection (defined as the presence of
hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be
obtained in these patients prior to Cycle 1, Day 1, but detection of HBV DNA in these
patients will not exclude study participation.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
chain reaction is negative for HCV RNA.
- Active tuberculosis
- Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
- Prior allogeneic stem cell or solid organ transplant
- Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
anticipation that such a live attenuated vaccine will be required during the study.
Inactivated vaccines (such as hepatitis A or polio vaccines) are permitted during the
- Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live attenuated influenza vaccine (e.g.,
FluMist) within 4 weeks prior to Cycle 1, Day 1 and for at least 12 weeks after the
- Clinically significant active infection or uncontrolled medical condition
- Uncontrolled cystitis, significant bladder pain or spasms, or gross hematuria that in
the opinion of the treating investigator, should preclude study entry.
- Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction within the previous 3 months, unstable
arrhythmias, or unstable angina
- Patients with known coronary artery disease, congestive heart failure not meeting the
above criteria, or left ventricular ejection fraction < 50% must be on a stable
medical regimen that is optimized in the opinion of the treating physician, in
consultation with a cardiologist if appropriate.
- Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day
1 or anticipation of need for a major surgical procedure other than cystectomy during
the course of the study
- Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF]
agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for
systemic immunosuppressive medications during the trial
- Patients who have received acute, low-dose, systemic immunosuppressant medications
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after
discussion with and approval by the Study Chair.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for
adrenal insufficiency) is allowed.
- Pregnant or nursing women are excluded
- Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component
of the MPDL3280A formulation
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
- Malignancies other than UC within 5 years prior to Cycle 1, Day 1, with the exception
of those with a low risk of metastasis or death treated with expected curative outcome
(such as, but not limited to, adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated with curative
intent and absence of PSA relapse, or ductal carcinoma in situ of the breast treated
surgically with curative intent) or incidental prostate cancer (T1a, Gleason score ≤ 6
and PSA < 0.5 ng/mL).
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Lawrence Fong, MD
Role: Principal Investigator
Affiliation: University of California, San Francisco